Method for rearing ruminants

ABSTRACT

THE RUMINANT FEED, FEED ADDITIVE OR VETERINARY COMPOSITION, COMPRISING A COMPOUND HVING THE FORMULA   R1,R2,(AM-ALK-O-),((R3,R4,R5-PHENYL)-X-)BENZENE   R1-4=H, ALKYL, HALOGENO, CF3 R5=H OR -O-ALK-AM X=DIRECT BOND, S,SO,SO2 OR ALKYLIDENE ALK=LOWER ALKYLENE AM=DI-LOWER ALKYLAMINO, LOWER ALKYLENEIMINO, MORPHOLINO OR 4-LOWER ALKYL-PIPERAZINO. OR AN ACID ADDITION SALT THEREOF, AND AN INGESTIBLE CARRIER MATERIAL, INCREASES THE PROPIONIC-ACETIC ACID RATIO IN THE RUMEN.

United States Patent "ice Int. Cl. A61k 27/00 US. Cl. 424-330 I 9 Claims ABSTRACT OF THE DISCLOSURE The ruminant feed, feed additive or veterinary composition, comprising a compound having the formula R 0-alk-Am R =H, alkyl, halogeno, CF,

X=direct bond, S, SO, S0 or alkylidene allc=lower alkylene Am=di-lower alkylamino, lower alkyleneimino, morpholino or 4-lower alkyl-piperazino.

or an acid addition salt thereof, and an ingestible carrier material, increases the propionic-acetic acid ratio in the rumen.

BACKGROUND OF THE INVENTION It is known that ruminal fermentation carries with it the advantages of high efliciency of utilization of poor quality fodder and the conversion of protein of low biological value to protein of a very much higher biological value. However, the price paid by the animal for these advantages in terms of energy utilization is quite high. It is that of maintaining a microbial population in the rumen at the expense of degradation of carbohydrate to volatile fatty acids plus the energy expenditure involved in reconverting fatty acids to carbohydrate required for normal mammalian metabolism. Therefore, we must assume that the bulk of the carbohydrate required (by the ruminant) must be resynthesized from propionic acid. (R. W. Dougherty et al., Physiology of Digestion in the Ruminant, Butterworths, 1965, page 304). Of the volatile fatty acids found in the rumen, acetic and propionic acids are those inter alia, present in the highest concentration. Since the latter plays the major role in gluconeogenesis, it is desired to artificially enhance the propionic-acetic acid ratio in the rumen, in order. to increase the average growth and weight gain of ruminants, such as cattle, shee or goats, as well as their feed conversion.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of a ruminant feed, feed-additive or veterinary composition, comprising a compound having the Formula I R O- alk-Am in which each of R R R and R stands for hydrogen, lower alkyl, halogen or trifluoromethyl, X for a direct 3,659,020 Patented Apr. 25, 1972 bond, thio, sulfinyl, sulfonyl or lower alkylidene, preferably methylidene, 2-propylidene or l-butylidene, R for the radical AmalkO- or, in case X stands for lower alkylidene, also for hydrogen, alk for lower alkylene separating the adjacent groups by at least 2 carbon atoms, Am for di-lower alkylamino, lower alkyleneimino, morpholino or 4-lower alkyl-piperazino, or an acid addition salt thereof, together with an ingestible carrier material, as Well as of a method of rearing ruminants with the use of said feed. It increases growth rate and feed efficiency, and prevents bloat.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of Formula I are described in Patent No. 3,332,958, as well as Patents Nos. 3,449,418 and 3,488,357.

Especially valuable are compounds of the Formula I, in which each of R and R stand for Z-methyl, each of R and R for S-methyl or S-tert. butyl, each of R and Oalk--Am for 4-(3-dimethylaminopropoxy) and X for a direct bond, thio or l-butylidene, as well as those-of Formula I, in which each of R R R and R stand for hydrogen, R for hydrogen or 4-chloro, OalkAm for 4-(2-diethylaminoethoxy) and X for Z-propylidene. They markedly enhance the propionic-acetic acid ratio of the rumen fluid of cattle and sheep fed normal diets. They furthermore reduce foam generated by a certain protozoan population present in the rumen. This can be demonstrated in in vivo or in vitro tests using .withdrawing samples of fistulated animals. In the former tests, the volatile fatty acids are determined directly in the rumen fluid, whereas in the latter the active substances are added to the rumen fluid, the whole is allowed to ferment under conditions coming close to those existing in the rumen, whereupon the volatile fatty acids are determined.

It has further been observed that to achieve the effects of the'invention the amount of said active substances present in the feed advantageously should range between about 0.001 to about 1.0 g./kg. of feed, preferably between about 0.01 to about 0.5 g./kg. Instead of the pure compounds, also corresponding concentrates or sludges may be used.

The ingestible carrier material used for the present ruminant feed or the additives to said feed, depends on the kind of animal to which such feed is to be given, on its age, the current market price of the material concerned and on several other factors. In general, a feed containing (besides the above-mentioned active ingredients) the usual balance of fats, carbohydrates, proteins, vitamins and minerals, is very advantageous. Suitable feed components are, for example, grain, such as rye, wheat, barley, oat or corn and mill products thereof, such as grain groats, meal or bran; roughages, such as grass, clover, milo, alfalfa, green oat or corn, which may be in the form of pasture, hay or silage; molasses or beet pulp, soybean or cotton seed meal, limestone meal, urea, mineralized salt and the like. Alternatively, the active ingredients may be administered in the form of a solution or dispersion with potable water or skimmed milk, if desired in the presence of a suitable dispersing agent, as additive or veterinary compositions, for example mixed with sugar and/or medicinal carbon, in the form of micropills or the like.

Apart from the aforementioned active substances, the feed and feedstuff additives according to the invention may contain further valuable substances, for example, antibiotics having a Wide activity spectrum, such as tetracycline, nonactin, oleandomycin or longisporine; hormones or other compounds having hormone action, such as diethyl-stilbestrol or hexestrol; enzymes; antiparasitic agents; substances useful in the breeding of ruminants; as 'well as preservants, such as benzoic acid. Such substances are well known in the art and their use is well documented in numerous scientific papers.

The growth-promoting compounds of this application are administered orally by combining the specified quan: titieswith a complete feed or feed supplement for ruminants, If desired, these compounds can be incorporated in other nutrient materials fed to ruminants, in the water or any ingestible, nontoxic, inert carrier material.

, The following examples illustrate the invention and are not to be construed as being limitations thereon.

-Procedure: The feed ingredients, except 1.0 kg. of barley, are thoroughly mixed in a horizontal mixer. The dihydrochloride is premixed With 1.0 kg. of finely ground barley and added to the main batch and the Whole is fur-. ther mixed until all ingredients are equally distributed in the feed.

I EXAMPLE 2 Sheep ration containing 0.05% of the active ingredient Formula: Kg. 2-[4-(2 diethylamino-ethoxy)-phenyl] 2 (4-chloro-phenyl)-propane hydrochloride 0.1 Ground grass-legume hay 50.0

Cracked yellow corn 134.3

Soybean meal (44% protein) 10.0 Cane molasses 2.0, Limestone meal 1.5 Trace mineralized salt 2.0

Procedure: The hydrochloride is premixed with 1.0 kg. of the soybean meal which is then mixed thoroughly with the remainder of the ration.

EXAMPLE 3 In the manner described in the previous examples the following active compounds are employed:

(a) 1,1-bis-[4-(3-dimethylamino-propoxy)-2-methyl-5- tert. butyl-phenyH-n-butane dihydrochloride,

(b) bis-[4-(3-dimethylamino-propoxy) 2,5-dimethylphenylj-sulfide dihydrochloride,

(c) 4,4'-di-(3-dimethylamino-propoxy)-2,2'-dimethyl- '5,5"-di-tert. butyl-biphenyl dihydrochloride and (d) 2-phenyl-2- [4-(Z-diethylamino-ethoxy) -phenyl1- propane hydrochloride EXAMPLE 4 The active ingredients mentioned above can be prepared according to the procedures disclosed in the patent and. applications mentioned in the beginning, e.g. as follows:

(A) To the solution of 12.33 g. 2-(4-chlorophenyD-2- (4-hydroxyphenyl)-propane in a mixture of "75 ml. dimethylformamide and 40 ml. toluene is added in portions 2.4 g. of a 53% suspension of sodium hydride in mineral oil While stirring and cooling. After the hydrogen evolution ceases, a solution of 7.0 g. Z-diethylaminoethyl chloride in 35 ml. toluene is added dropwise while stirring and cooling. Stirring is continued for an additional three hours at room temperature, and the reaction mixture is then allowed to stand at that temperature for fifteen hours.

The inorganic precipitate is filtered off, the filtrate'is conentrat d to a meo ab u 0 80ml. di uted. w th water and extracted with 300 m1. diethyl ether. The extract is separated and washed with 100 ml. of 2 N aqueous hydrochloric acid; the acid solution is separated, and after a few minutes, the 2-(4-chlorophenyU-2- [4-(2-diethylaminoethoxy) -phenyl]-propane hydrochloride of the formula Y precipitates. t is. co e ed and e ta l d ram a We f nol nd dieth l th r. M1 1 055-186." iel 18.7 g.

The starting material used is prepared as follows: To the ice-cooled Grignard reagent, prepared from 284.0 g. methyl iodide and"48.6. g. magnesium turnings in 550 m1. diethyl ether, is added dropwise a solution of 154.6 g. 4- chloro-acetophenonev in 20.0 ml. diethyl ether while stirring. The reaction mixture is allowed to stand at room temperature and is then heated to reflux for two hours. The Grignard complex is decomposed by slowly adding 300 ml. of a saturated aqueous solution of ammonium chloride and 300 ml. water while stirring and cooling in an ice bath, 300 ml. diethyl ether are added and the organic layer is separated, washed and dried over sodium sulfate. T he solvent is removed, and the 2-.(4-chlorophenyl)-2-propanol is obtained by distilling the residue, B, P. 9 2-96/3 mm. Hg. 0

T e, xt r o 7-1 he eo and 9- s.- j fl s added portionwise to the mixture of 28.2 g. phenol and 6 .7 g. aluminum chloride while stirring and cooling With water. The reaction mixture is stirred at room temperature for two hours, allowed to stand for fifteen hours and is then heated for one hour to 40-50 while stirring. It is added to 100. ml. of 6 N aqueous hydrochloricacid while stirring; the organic layer is separatefiand the excess phenol is removed by distillation at temperatures up to 13.0./ 13 mm. Hg. The oily residue is distilled to yield the 2 (4.- chlorophenyl)-2-(4-hydroxyphenyl)-propane,

I which crystallizes from hexane, MP. 727 4.

(B) To a solution of 9.6 g. l,l-di(4-hydroxy-2-meibyl1 S-tert. butyl-phenyD-n-butan: in 25 m1. dimethyl forniamide and 45 ml. toluene, 2.25 g. of a 53% suspension of sodium hydride in mineral oil are added gradually with stirring in an atmosphere of nitrogen. Afterstirring for one hour at room temperature a solution of 6.7 3.-dimethylamino-p-ropyl chloride in 55 ml. toluene is added and the reaction mixture is kept at 80 for 8 hours. After cooling, it is filtered and concentrated in vacuo. The residue is dissolved in diethyl ether, the solu i tion washed with water, dried andconcentrated. The concentrate is dissolved in ethyl acetate and a solution of hydrogen chloride in ethyl acetate is added. The pre: cipitate formed is filtered off and recrystallized from isopropanol-ethyhacetate. There is obtained the l,1- di-[4 (3-dimethylamino-propoxy) 2 methyl 5 tert. buty lw phenyl1-n-butane dihydrochloride of the formula cs cs orally administering to said ruminant, a feed composition,

comprising between about 0.001 to about 1.0 gram of a compound having the formula l e A '11: o X

in which Am stands for di-lower alkylamino, lower alkyleneimino, morpholino or 4-lower alkyl-piperazino, alk for lower al'kylene separating the adjacent groups by at least 2 carbon atoms, each of R R R and R for hydrogen, lower alkyl, halogen or trifluoromethyl, X for a direct bond, thio, sulfinyl, sulfonyl or lower alkylidene and R for the radical AmalkO or, in case X stands for lower alkylidene, also for hydrogen, or an acid addition salt thereof per kilogram of ruminant feed.

2. The method as claimed in claim 1, in which formula of the active ingredient each of R and R stand for 2- methyl (each of R and R for S-methyl or S-tert. butyl, propoxy) and X for a direct bond, thio or l-butylidene.

3. The method as claimed in claim "1, in which formula of the active ingredient each of R R R and R stand for hydrogen, R for hydrogen or 4-chloro, OalkAm for 4-(2-diethylaminoethoxy) and X for Z-propylidene.

4. The method as claimed in claim 1, wherein the active ingredient is the bis[4 (3 dimethylamino-propoxy)-2- methyl-S-tert. butyl-phenyl]-sulfide or its dihydrochloride.

5. The method as claimed in claim 1, wherein the active ingredient is the 2 [4 (2-diethylamino-ethoxy)- phenyl]-2-(4-chloro-phenyl)-propane or its hydrochloride.

6. The method as claimed in claim 1, wherein the active ingredient is the 1,1-bis-[4-(3-dimethylamino-propoxy)-2- methyl 5 tert. butyl-phenyH-n-butane or its dihydrochloride.

7. The method as claimed in claim 1, wherein the active ingredient is the bis-[4-(3-dimethylamino-propoxy)- 2,5-dimethylphenyl]-sulfide or its dihydrochloride.

8. The method as claimed in claim 1, wherein the active ingredient is the 4,4'-di-(3-dimethylamino-propoxy)-2,2- dimethyl-S ,5 -di-tert. butyl-biphenyl or its dihydrochloride.

9. The method as claimed in claim 1, wherein the active ingredient is the 2 phenyl 2-[4-(2-diethylaminoethoXy)-phenyl]-propane or its hydrochloride.

References Cited UNITED STATES PATENTS 3,488,357 1/ 1970 Bencze 260294.7 3,332,958 7/1967 Werner 260-295 3,449,418 6/1969 Werner 260559 SAM ROSEN, Primary Examiner US. Cl. X.R. 424-248, 250

22 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 31 595 I Dated April 25, 1972,

Inventor) DOUGLAS CECIL MAPLESDEN ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, lines L and 5, delete "Ciba Corporation, Summit,

NJ. and substitute CIBA-GEIGY Corporation, Ardsley, New York ---5 l Column 5, line 20, delete and insert before line 2l,insert ea.ch of R and O-alk-Am for L-(S-dimethylaminm Y line 27, after 'bis" insert Signed and sealed this 11th day of 11111619714.

(SEAL) Attest:

C. MARSHALL DANN EDJARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer 

